Advancements in Macrophage-Targeted Drug Delivery for Effective Disease Management.

Macrophages play a crucial role in tissue homeostasis and the innate immune system. They perform essential functions such as presenting antigens, regulating cytokines, and responding to inflammation. However, in diseases like cancer, cardiovascular disorders, and autoimmune conditions, macrophages undergo aberrant polarization, which disrupts tissue regulation and impairs their normal behavior. To address these challenges, there has been growing interest in developing customized targeted drug delivery systems specifically designed for macrophage-related functions in different anatomical locations. Nanomedicine, utilizing nanoscale drug systems, offers numerous advantages including improved stability, enhanced pharmacokinetics, controlled release kinetics, and precise temporal drug delivery. These advantages hold significant promise in achieving heightened therapeutic efficacy, specificity, and reduced side effects in drug delivery and treatment approaches. This review aims to explore the roles of macrophages in major diseases and present an overview of current strategies employed in targeted drug delivery to macrophages. Additionally, this article critically evaluates the design of macrophage-targeted delivery systems, highlighting limitations and discussing prospects in this rapidly evolving field. By assessing the strengths and weaknesses of existing approaches, we can identify areas for improvement and refinement in macrophage-targeted drug delivery.

The association between fatty liver index and onset of diabetes: secondary analysis of a population-based cohort study.

BACKGROUND: According to research, the fatty liver index (FLI) is associated with diabetes. However, few studies have been conducted to investigate the relationship between FLI and diabetes risk from various perspectives. This study comprehensively investigated the relationship between FLI and incident diabetes in a large Japanese population. METHODS: This retrospective cohort study included 14,280 participants from Murakami Memorial Hospital in Japan from 2004 to 2015. The independent and dependent variables are FLI and risk of type 2 diabetes mellitus (T2DM), respectively. To examine the link between FLI and incident T2DM, Cox proportional-hazards regression was employed. In addition, we performed a number of sensitivity studies to guarantee the validity of the results. Moreover, we conducted subgroup analyses. RESULTS: After adjusting covariates, the results showed that FLI was positively associated with the risk of T2DM (HR = 1.019, 95%CI: 1.012, 1.025). Additionally, the sensitivity analysis showed how reliable the outcomes were. And a stronger association between FLI and incident T2DM was observed in the regular exercisers (HR = 1.036, 95%CI: 1.019-1.053, P < 0.0001) and the population without ethanol consumption (HR = 1.028, 95%CI: 1.017-1.039, P < 0.0001). Besides, receiver operating characteristic (ROC) curve analysis showed that FLI was better than waist circumference, triglycerides, body mass index, and gamma-glutamyl transferase in predicting incident T2DM. CONCLUSION: FLI is positively associated with incident T2DM.

Protective effects and potential mechanisms of fermented egg-milk peptides on the damaged intestinal barrier.

Introduction: Fermented egg-milk peptides (FEMPs) could enhance the colon-intestinal barrier and upgrade the expression of zonula occludens-1 and mucin 2. Besides, the underlying biological mechanism and the targets FEMPs could regulate were analyzed in our study. Methods: Herein, the immunofluorescence technique and western blot were utilized to evaluate the repair of the intestinal barrier. Network pharmacology analysis and bioinformatics methods were performed to investigate the targets and pathways affected by FEMPs. Results and discussion: Animal experiments showed that FEMPs could restore intestinal damage and enhance the expression of two key proteins. The pharmacological results revealed that FEMPs could regulate targets related to kinase activity, such as AKT, CASP, RAF, and GSK. The above targets could interact with each other. GO analysis indicated that the targets regulated by FEMPs could participate in the kinase activity of the metabolic process. KEGG enrichment revealed that the core targets were enriched in pathways related to cell apoptosis and other important procedures. Molecular docking demonstrated that FEMPs could bind to the key target AKT via hydrogen bond interactions. Our study combined the experiment in vivo with the method in silico and investigated the interaction between peptides and targets in a pattern of multi-targets and multi-pathways, which offered a new perspective on the functional validation and potential application of bioactive peptides.

Mechanism investigation of fermented egg-milk peptides on colonic inflammatory diseases: based on in vivo and in silico research.

Fermented egg-milk peptides (FEMPs) could alleviate the symptoms of inflammatory diseases but the underlying regulating mechanism of effective ingredients is unclear now. Our research was designed to confirm the protective function of FEMP, then analyze the potential targets and pathways that could be regulated by digested FEMP (dFEMP). The results showed that FEMP could ease the inflammatory symptoms in the colon, repair the damage of inflammation, and decrease the level of pro-inflammatory cytokines (decreased by 31.81% TNF-α, 60.20% IL-1ß, 85.65% IL-6). The results of in silico experiments revealed that dFEMP could influence many inflammation-related targets. Most targets affected the inflammation-related function and participated in the inflammatory signaling pathways, such as the T cell receptor (TCR) signaling pathway. Besides, molecular docking results revealed that hydrogen-bonding and salt bridges played vital roles in the dFEMP-target interactions. Combining in vivo experiments with in silico experiments, this study can prove a new theory for research between the bioactive peptides and inflammation.

m6A-induced repression of SIAH1 facilitates alternative splicing of androgen receptor variant 7 by regulating CPSF1.

Androgen receptor splice variant 7 (AR-v7), a constitutively active transcription factor, plays a crucial role in the progression of castration-resistant prostate cancer (CRPC). Here, we found that the cleavage and polyadenylation specificity factor 1 (CPSF1) (the largest subunit of the multi-protein cleavage and polyadenylation specificity complex), regulated by the E3 ubiquitin ligases SIAH1, promoted AR-v7 expression. The data from microarray-based analysis and clinical specimen-based analysis showed that SIAH1 expression was decreased in PCa and was negatively correlated with aggressive phenotypes of PCa. SIAH1 repressed PCa cell growth and invasion under castrate conditions. SIAH1 directly interacted with CPSF1 and promoted ubiquitination and degradation of CPSF1. CPSF1 expression was negatively correlated with SIAH1 expression, but positively with PCa progression. CPSF1 overexpression switched the AR splicing pattern and facilitated the generation of the oncogenic isoform (AR-v7) by binding to the AAUAAA polyadenylation signal contained in AR-cryptic exon CE3. Functionally, SIAH1 acted as a tumor suppressor in PCa pathogenesis by repressing CPSF1-mediated AR-v7 generation. Finally, we demonstrated that m6A methylation was concerned with the repression of SIAH1 in PCa. Our results define SIAH1/CPSF1/AR-v7 axis as a regulatory factor of PCa progression, providing a promising target for treating PCa.

Fermented egg-milk beverage alleviates dextran sulfate sodium-induced colitis in mice through the modulation of intestinal flora and short-chain fatty acids.

Fermented egg-milk beverage (FEMB) can alleviate the symptoms of intestinal diseases by regulating intestinal flora and supplying nutrition. This study investigated the protective effect of FEMB on dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) in mice. The results showed that FEMB relieved the UC mice's pathological abnormalities and colonic inflammation, and restructured the intestinal flora composition simultaneously. After FEMB treatment for 14 days, the body weight of the mice rose and the disease activity index (DAI) value decreased. Furthermore, the length and form of colons in the UC mice were notably restored. Inflammatory cells decreased or disappeared, and goblet cells and crypt were enriched and modified. 16S rRNA gene sequencing results demonstrated that FEMB treatment could increase the abundance of beneficial bacteria in the cecum content of mice, including unclassified_f_Lachnospiraceae and Lactobacillus. Moreover, probiotics that can increase the content of short-chain fatty acids (SCFAs) may contribute to inflammation alleviation. An increase in amino acids was observed in our experiment, which may benefit nutritional supplements. In conclusion, FEMB treatment can alleviate the damage of DSS-induced colitis in Balb/c mice. This study provides a theoretical basis for both the relief of inflammation and the application of FEMB.

Granulocytic myeloid-derived suppressor cells correlate with outcomes undergoing neoadjuvant chemotherapy for bladder cancer.

OBJECTIVES: It remains unclear whether the immunologic status of cells in peripheral blood can be used as a prognostic indicator of response to treatment for patients with neoadjuvant chemotherapy (NAC). This study sought to evaluate whether the proportion of granulocytic myeloid-derived suppressor cells (G-MDSCs) and monocytic myeloid-derived suppressor cells could correlate with pathologic response in bladder cancer patients receiving NAC. PATIENTS AND METHODS: Pretreatment peripheral blood levels of G-MDSCs and monocytic myeloid-derived suppressor cells were measured by flow cytometry. We divided patients into high and low (above and below the median, respectively) groups based on the median value for each immune cell subset and compared outcomes of the two groups. RESULTS: A significant pathological response (pT0-1) was attained in 13% (6 of 45) of patients with high G-MDSCs compared with 58% (26 of 45) of patients with low G-MDSCs (P < 0.001). Patients with high G-MDSCs had significantly shorter disease specific survival and progression-free survival (both P < 0.001). In the multivariate analysis for survival, high G-MDSCs and pathological response emerged as independent prognostic factor for progression-free survival (P < 0.001 and P = 0.017) and disease-specific survival (P < 0.001 and P = 0.014). CONCLUSIONS: Pretreatment peripheral G-MDSCs may represent a potential marker for the outcome of patients treated with cisplatin-based NAC.

CD163+ macrophages predict a poor prognosis in patients with primary T1 high-grade urothelial carcinoma of the bladder.

PURPOSE: Macrophages are a major cell type that can infiltrate solid tumors and exhibit distinct phenotypes in different tumor microenvironments. This study investigates the prognostic value of tumor-infiltrated CD163+ macrophages in patients with T1 high-grade (T1HG) bladder cancer. METHODS: CD163+ macrophages were assessed by immunohistochemistry in 94 T1HG bladder cancer samples. Kaplan-Meier analyses and Cox proportional hazards' regression models were applied to evaluate recurrence-free survival, progression-free survival and disease-specific survival. RESULTS: With a median follow-up of 60 months, 37 (39.4%) patients experienced disease recurrence, 14 (14.9%) progression, 11 (11.7%) disease-specific mortality. High CD163+ macrophages were associated with higher risk of disease recurrence and progression (P < 0.05, for both). In multivariate Cox proportional hazards regression analysis, high CD163+ macrophages were a significant negative predictor of recurrence-free survival, progression-free survival and disease-specific survival (P < 0.05 for all). CONCLUSION: CD163+ macrophages are a poor prognostic factor in T1HG bladder cancer. This finding provide the ground for further testing it in predicting the outcome of this challenging disease.

A novel treatment strategy for newly diagnosed high-grade T1 bladder cancer: Gemcitabine and cisplatin adjuvant chemotherapy-A single-institution experience.

BACKGROUND: Management of high-grade T1 (formerly T1G3) bladder cancer continues to be controversial. Should patients with T1G3 bladder cancer have an immediate radical cystectomy or should they receive intravesical bacillus Calmette-Guérin-preserving bladder? Gemcitabine and cisplatin (GC) adjuvant chemotherapy may help to strike a balance between intravesical and early cystectomy. For purposes of this study, we continue to refer high-grade T1 lesion as "T1G3." OBJECTIVE: To evaluate the characteristics and the long-term outcome of GC adjuvant chemotherapy in T1G3 bladder cancer after transurethral resection of bladder tumor (TURBT). MATERIALS AND METHODS: We retrospectively reviewed 48 patients who were newly diagnosed with T1G3 bladder cancer between January 2009 and December 2012. A total of 48 patients received 4 cycles of GC adjuvant chemotherapy after TURBT. One month after 4 cycles of GC adjuvant chemotherapy, response was evaluated by re-TURBT. Median follow-up was 59.5 (range: 18-70) months, all patients have been observed for more than 3 years. Salvage cystectomy was recommended for patients with persistent disease and for tumor progression after initial complete response. RESULT: Complete response was achieved in 44 (91.7%) patients. Of complete responders, 5 patients experienced recurrence and 5 patients showed progression. The progression rate and disease-specific survival rate were 10.4% and 91.7% at 3 years, respectively. More than 80% of survivors preserved their bladder. Kaplan-Meier curves showed that concomitant carcinoma in situ (CIS) was the only factor that had an influence on progression-free survival (P = 0.022) and disease-specific survival (P = 0.017). Concomitant CIS was the prognostic factor for progression rate and disease-specific survival rate at 3 years (P = 0.008 and P = 0.035). CONCLUSION: GC adjuvant chemotherapy is a safe conservative treatment for T1G3 bladder cancer, but effective is really a phase II study. Patients with T1G3 bladder cancer with concomitant CIS should be treated more aggressively because of the high risk of progression.

Enzymatic synthesis of glutathione using engineered Saccharomyces cerevisiae.

Two single gene cassettes, each containing one of the individual gene (γ-glutamylcysteine synthetase gene GSH1 or glutathione synthetase gene GSH2), were constructed under the control of alcohol dehydrogenase (ADH1) promoter and their respective native terminators. The recombinant plasmids constructed with Kan (r) or Hyg (r) as the selective markers and were transformed into Saccharomyces cerevisiae separately and jointly. Three engineered strains, GSH1-enhanced strain S.TS013/GSH1, GSH2-enhanced strain S.TS013/GSH2 and GSH1+GSH2 double-enhanced strain S.TS013/GSH1+GSH2, were constructed. Glutathione production using the recombinant strains to improve was then determined. By the cell dosage proportions of two engineered strains (S.TS013/GSH1, S.TS013/GSH2) and a two-stage reaction, GSH productivity increased by 84 and 59 % over that of the host strain and the S.TS013/GSH1+GSH2 strain, respectively.